ABSTRACT Liver regeneration enables living donor liver transplantation and is fundamental to repair after liver injury. However, aberrant repair processes, as in the setting of chronic injury due to hepatitis or obesity, can lead to cirrhosis and liver cancer. Considerable research effort, including our own, seeks to clarify fate relationships among cell types involved in liver regeneration, including hepatocytes, cholangiocytes, and stellate cells. However, key knowledge gaps persist regarding mechanisms controlling these cells' plasticity. Further, although an array of signaling pathways have been implicated in liver repair, how these are integrated to specify and maintain progenitor fate within the liver remains unknown. Our ultimate goal is to delineate the mechanisms that control liver regeneration so this knowledge can be applied to prevent and treat key consequences of mis-repair. Our work to date has shown that (1) the Hedgehog (Hh) pathway directs adult liver repair by controlling the size of liver progenitor and myofibroblast (MF) populations; (2) activating the pathway in Hh-responsive cells drives them to become more primitive (i.e., less differentiated, more glycolytic, proliferative, migratory, and fibrogenic), and silencing Hh signaling has the opposite effects; (3) hepatic stellate cells (HSC) are liver-resident members of a network of Hh-responsive perivascular cells (i.e., pericytes) that appear to retain mesenchymal stem cell traits (also reported by others); and (4) in extensive data underpinning our current proposal, Hh signaling interacts with the Hippo/YAP pathway, a distinct developmental pathway known to help control fate decisions in mesenchymal stem cells and to control adult liver growth by regulating liver progenitor population size. However, it is unknown how the Hh-YAP collaboration causes HSC reprogramming or why this is necessary for liver repair. Based on work by us and others, our hypothesis is that Hedgehog activates YAP in HSC to optimize accumulation of MF-HSC that enhance growth of cells with liver repopulating capacity, and this process requires Hh/YAP-dependent reprogramming of HSC through metabolism changes. Our aims will elucidate the functional consequences of Hh-YAP cross-talk on liver repair and will clarify energy-related mechanisms that coordinate this cross-talk. Each Aim addresses a key question: How do reprogrammed HSC control hepatocyte plasticity during liver repair? How does Hh reprogram HSC during liver repair? How does Hh interact with YAP to reprogram HSC into proliferative MF? Successful completion of these aims will deepen understanding of mechanisms that co-regulate Hedgehog and YAP/Hippo to achieve effective liver repair. This knowledge will clarify how this intricate process goes awry during human liver disease, and enable development of interventions to enhance appropriate regeneration. Our strong preliminary data and experienced and productive research team position us for success.